DESCRIPTION: (Applicant's Description) Altered expression of the c-myc proto-oncogene has been observed in nearly one seventh of fatal cancers in the United States, implying a fundamental involvement of c-myc in cancer. c-myc encodes a transcription factor of the basic helix-loop-helix/leucine zipper type. A major unresolved dilemma in understanding the role of c-Myc in cancer is determining how its oncogenic function is related to its activity as a transcriptional regulator and to its function in normal cells. Drosophila melanogaster is a superb system in which to carry out functional and genetic studies of protein function in vivo. Further, the high degree of structural conservation of proteins in flies and vertebrates provides assurance that the mechanisms and genes discovered in Drosophila are likely to perform similar functions in humans. To initiate a genetic analysis of the function of Myc proteins in the Drosophila system, we and our collaborators isolated the Drosophila homologue of the human c-myc gene, d-myc, and demonstrated that it corresponds to the product of a known Drosophila gene, diminutive (dm). We have subsequently generated additional, lethal mutations in dm. To begin a structure/function analysis of the Drosophila c-Myc homolog, we will first determine the changes in the protein coding sequence that correspond to the new, lethal mutations in dm. Our second specific aim will determine the in vivo consequences of the loss of d-myc function using the newly generated lethal alleles of dm. Zygotic mutants for these alleles, which do not develop beyond the first larval instar, and homozygous mutant clones in the eye will be characterized with markers for cell size, cell division, DNA replication and apoptosis. The requirement for d-myc expression during oogenesis will be examined in females carrying germline or follicle cell clones of dm mutations. The third specific aim of this proposal will identify genes encoding proteins that either regulate d-Myc expression or function, or are themselves targets of d-Myc transcriptional activity by carrying out genetic screens for modifiers of d-myc-related phenotypes in the ovary and eye. We anticipate that this work will not only provide a means to test current hypotheses regarding the function of c-Myc, but will also identify novel genes and pathways involved in regulating the c-Myc network. In addition to providing valuable insights into the normal function of c-Myc, we are optimistic that new directions for therapeutic interventions of cancer will be suggested through the enhanced understanding of c-Myc regulators and effectors that will be achieved via the genetic analysis of the Drosophila c-Myc homolog.